Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia
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ABSTRACT:
PROVIDER: PRJNA729777 | ENA |
REPOSITORIES: ENA
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Project description:We examined the effects of antipsychotic medications on the cell-specific epigenomics and transcriptomics in the frontal cortex of schizophrenic subjects.
2021-11-05 | GSE174407 | GEO
Project description:Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments showed thioridazine and olanzapine constituted a robust cluster. K-means clustering separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups. Keywords: repeat sample
2004-09-24 | GSE1501 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE38481: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanRef-8 v3.0] GSE38484: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanHT-12 V3.0] Refer to individual Series
2012-07-08 | E-GEOD-38485 | biostudies-arrayexpress
Project description:Multiple studies have shown that brain gene expression is disturbed in subjects suffering from schizophrenia. However, disentangling disease effects from alterations caused by neuroleptics is a challenging task. <br> To address the issues of disease heterogeneity and the effect of antipsychotic medication, we use a large collection of 110 brain autopsy samples, subdivided according to the type of antipsychotic medication received. We use global and high-resolution mRNA quantification techniques to analyse gene expression in brain tissues. We also analyse transcription in-vitro, in cell lines before and after treatment with cytokines.<br> Results. We show that inflammation-related genes are up regulated in all groups of patients, including those not treated at the time of death. In particular, four co-expressed genes that are inducible by inflammatory cytokines showed increased mRNA levels, namely IFITM2, IFITM3, SERPINA3, and GBP1 (p-values from qPCR ? 0.01). We also show that these genes are expressed in oligodendrocyte and endothelial cell lines, and transcription is inducible by inflammatory cytokines in both cell lines. Our results give molecular support to the inflammatory theory of schizophrenia and suggest that inflammatory cytokines may stimulate transcription in endothelial brain cells during schizophrenia progression. Unexpectedly, inflammation-related genes may also have a role in myelin producing cells, since they are also inducible by cytokines in oligodendrocyte cell lines. Our findings encourage future research to explore whether anti-inflammatory agents can be used in combination with traditional antipsychotics for a more efficient treatment of schizophrenia.
2007-12-06 | E-MEXP-857 | biostudies-arrayexpress
Project description:In pevious research we have shown that the disruption of the normal development of the ventral hippocampus in rodents leads to cellular abnormalities in the frontal cortex and behavioral deficits related to schizophenia (Neurotox Res. 2002, 4(5-6):469-475). We propose the use of gene expression analysis to investigate the molecular underpinnings of these processes which may shed light on the molecular processes relevant to human schizophrenia. In addition, we seek to characterize expression differences induced by chronic administration of antipsychotic medications, which may give insight into the molecular processes involved in ameliorating psychotic symptoms. Using both surgical and drug interventions, we aim to examine experimentally induced expression differences in the rodent brain that are relevant to human neuropsychiatric disorders. Disruption of the normal development of the vental hippocampus or chronic neuroleptic administration, will result in gene expression changes in the frontal cortex of rats. Elucidation of the molecular cascades underlying these treatments will shed light on both the pathoetiology (from the lesion experiments) and theurapeutic processes (from the antipsychotic treatment experiments) involved in human schizophrenia. We have developed 3 groups of samples:; 1] Ventral hippocampal lesion in neonatal rats (treatment and controls, total N=22); 2] Tetrodotoxin disruption of the ventral hippocampus (treatment and controls, total N=20); 3] Chronic administration of neuroleptics (multiple drugs, multiple doses, and controls, total N=63) Grand Total N=105
2008-06-12 | E-GEOD-4031 | biostudies-arrayexpress
Project description:Background. Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell, and pharmacological studies suggest an important overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics in medium spiny neurons (MSNs). Methods. We applied single-cell RNA-sequencing to striatal samples from C57BL/6J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We implemented careful statistical analyses to identify differentially expressed genes in two cell populations identified from the single-cell RNA-sequencing (MSNs and microglia) and applied multiple analysis pipelines to contextualize these findings. Results. Differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) in MSNs from mice treated with olanzapine vs. haloperidol. DEGs were enriched in broad loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses highlighted alternative splicing, mitochondrial function, and neuron and synapse development as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. Conclusions. Our goal was to evaluate connections between schizophrenia genetic findings and cellular gene expression changes following antipsychotic exposure. We found that differential gene expression in MSNs from mice chronically treated with olanzapine converges on similar pathways and gene sets.
2021-04-14 | GSE171977 | GEO
Project description:Genetic and molecular studies have implicated the bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioural phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of actin cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.
2019-01-07 | PXD009689 | Pride
Project description:Genetic and molecular studies have implicated the bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioural phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of actin cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.
2019-01-07 | PXD009688 | Pride
Project description:DNA methylation (DNAm) is important in brain development, and potentially in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia, and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape, and overlap regions of genetic risk for schizophrenia. A quarter of published GWAS-suggestive loci (4,208/15,930, p<10-20) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls, enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci, while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.
2015-10-21 | GSE74193 | GEO
Project description:The dorsolateral prefrontal cortex (DLPFC) is the association area in the anterior part of the frontal lobe and has a crucial role in cognitive functioning and negative symptoms in SZschizophrenia. However, limited information of altered protein networks is available in this region in schizophrenia. We performed a proteomic analysis using single-shot liquid chromatography-tandem mass spectrometry of grey matter of postmortem DLPFC in chronic schizophrenia subjects (n=20) and healthy individuals (n=20) followed by bioinformatic analysis to identify altered protein networks in SZ.
2023-05-10 | PXD024939 | Pride